SAKK 35/14 Rituximab in Kombination mit Ibrutinib oder Placebo in nicht vorbehandelten Patienten mit einem fortgeschrittenen follikulären Lymphom mit Therapiebedarf. Eine randomisierte, doppelblindePhaseIIStudie

Drug: Ibrutinib;Drug: Rituximab

Gender: All
Maximum age: 85 Years
Minimum age: 18 Years

Inclusion Criteria:

- Written informed consent according to ICH/GCP guidelines

- Histologically confirmed FL CD20+; grade 1, 2, 3a; stage III+IV; stage II not suitable
for radiotherapy; all FLIPI

- Tumor specimens (slides or block) available for pathological review

- In need of systemic therapy (at least one of the following indications must be
fulfilled):

- Symptomatic disease

- Bulky disease (= 6 cm)

- Steady, clinically significant progression over at least 3 months of any tumor
lesion

- B-symptoms (weight loss > 10% in 6 months, drenching night sweats, fever > 38?C
not due to infection)

- Anemia (hemoglobin < 100 g/L) or thrombocytopenia (platelets 50-100 x 109/L) due
to lymphoma

- At least one two-dimensionally measurable lesion with a longest diameter (LDi) = 15 mm
in contrast-enhanced 18F-FDG PET/CT* scan

- FDG-avid tumor lesion in contrast-enhanced 18F-FDG PET/CT* scan

- Age 18-85 years

- WHO performance status 0-2

- Adequate bone marrow function:

- Absolute neutrophil count (ANC) > 1.0 x 109/L independent of growth factor
support

- Platelets = 100 x 109/L or = 50 x 109/L if bone marrow involvement independent of
transfusion support in either situation

- Adequate hepatic function:

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3 x upper
limit of normal (ULN)

- Total bilirubin = 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or
of non-hepatic origin

- Adequate renal function:

? Serum creatinine = 2 x ULN and corrected calculated creatinine clearance = 40
mL/min/1.73m2.

- Women of childbearing potential have a negative serum (beta-human chorionic
gonadotropin) or urine pregnancy test at Screening.

- Patient compliance and geographic proximity allow proper staging and follow-up.

Exclusion Criteria:

- Tumor bulk requiring fast response

- Known central nervous system lymphoma

- Previous systemic FL therapies

- Major surgery 4 weeks prior to randomization

- Previous or concomitant malignancy diagnosed within 3 years with the exception of
adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer

- History of stroke or intracranial hemorrhage within 6 months prior to randomization

- Clinically significant cardiovascular diseases such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by
the New York Heart Association Functional Classification

- Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or
active Hepatitis B Virus infection or any uncontrolled active systemic infection
requiring intravenous (i.v.) antibiotics

- Concomitant diseases that require anticoagulation with warfarin or equivalent vitamin
K antagonists (eg. phenprocoumon), factor Xa inhibitors (e.g. rivaroxaban, apixaban),
direct thrombin inhibitors (e.g. dabigatran) or platelet inhibitors/antiplatelet
agents. Aspirin is allowed (up to 300 mg/d).

- Concomitant diseases that require treatment with strong or moderate CYP3A inhibitors
(see http://medicine.iupui.edu/clinpharm/ddis/clinical-table/)

- Any concomitant drugs contraindicated for use with the trial drugs according to the
approved product information or known hypersensitivity to trial drugs

- Concurrent treatment with other experimental drugs or other anticancer therapy,
treatment in a clinical trial within 30 days prior to trial entry

- Vaccinated with live, attenuated vaccines 4 weeks prior to randomization

- Any life-threatening illness, medical condition, or organ system dysfunction which, in
the Investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of Ibrutinib capsules, or put the study outcomes at undue
risk

- Psychiatric disorder precluding understanding information of trial related topics,
giving informed consent or interfering with compliance for oral drug intake

- Women who are pregnant or breastfeeding

- Patients regularly taking corticosteroids during the last 4 weeks, unless administered
at a dose equivalent to Prednisone = 15 mg/day for indications other than lymphoma or
lymphoma-related symptoms